Multiple Sclerosis (MS) is a T-cell mediated autoimmune demyelinating disease of the central nervous system (CNS) of unknown etiology (1-3), and often presents in several clinically distinct forms. For example, relapsing remitting multiple sclerosis (MS) is characterized by T-cell induced autoimmune destruction of the myelin sheath and produces relapsing and remitting attacks of neurological dysfunction (RRMS) (1-3), which is typically followed by a secondary progressive neurodegenerative phase (SPMS), distinguished by axonal damage and neuronal loss (2). Primary progressive MS (PPMS) is similar to SPMS but lacks the initial relapsing-remitting phase.
With adult onset and partially familial relationships, causality is thought to result from complex interactions between environmental and genetic factors (1,6,7). Whole genome screens have identified a number of candidate loci associated with MS (8) and the animal model EAE (9, 10), which are typically MHC-related genes. However, non-MHC genes with strong association to MS have yet to be identified as such genes may correlate to the suspected environmental component of the MS etiology.
Golgi β1-6 N-acetylglucosaminyltransferase V (Mgat5) is a potent negative regulator of TCR signaling, T-cell proliferation, TH1 differentiation and autoimmunity (e.g., involved in EAE, a murine model of MS) (4,5). Mgat5-modified N-glycans are extended with poly-N-acetyllactosamine sequences, which are preferred ligands for galectins. Mgat5 N-glycans on T cell receptor (TCR) hind multi-valent galectins, thus restricting TCR recruitment into the immune synapse (4). It should be noted that myelin-specific transgenic mice develop spontaneous CNS autoimmune demyelinating disease (11-14), but spontaneous disease secondary to physiologically-relevant gene dysfunction has not been reported.
Diagnosis of MS is often based on several individual potential markers, and most commonly focus on identification of specific nucleic acids as described in U.S. Pat. No. 6,933,119 to Leppert et al. or U.S. Pat. No. 6,001,978 to Perron. Other known diagnostic assays involve detection of specific polypeptides as described by Kline in U.S. Pat. No. 5,883,227, or on T-cell subpopulation measurement as taught in U.S. Pat. No. 4,677,061. Still further known diagnostic tests are based on tests of human motor function as described in U.S. Pat. No. 6,702,756.
Similarly, numerous chemically distinct treatment modalities for MS have been proposed. Among many other compounds, modified adenine derivatives were employed as described in U.S. Pat. No. 5,506,214, while heterocyclic phospholipids were proposed as therapeutic agents in U.S. Pat. No. 5,064,816. In yet other examples of pharmaceutical active compounds for treatment of MS, chloroquine was presented in U.S. Pat. No. 5,624,938, and aloe vera products were described as therapeutic agents in U.S. Pat. No. 5,780,453. Still further known compositions for treatment of MS include peptide analogues as taught in U.S. Pat. No. 5,948,764, estriol as described in U.S. Pat. No. 6,936,599, and various tetracycline derivatives as taught in U.S. Pat. No. 6,613,756.
As will be readily apparent to the person of ordinary skill in the art, such vast disparity in proposed active ingredients for treatment of MS and disparate markers strongly suggest a multi-factorial etiology, a potentially complex underlying metabolic system, and/or a general lack in the interplay of environmental factors and underlying genetic disposition.
Thus, while numerous compositions and methods for diagnosis, prevention, and treatment of MS and other autoimmune diseases are known in the art, all or almost all of them, suffer from one or more disadvantages. Therefore, there is still a need for improved pharmaceutical agents for treatment and chemoprevention of MS and other autoimmune diseases.